RESUMEN
Correction to: Oncogene (2013) 32, 23042314; doi:10.1038/onc. 2012.248; published online 18 June 2012. Since the publication of the above paper, the author listed as C Ryan Miller has requested that the listing of his name be changed to CR Miller.
RESUMEN
Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is silenced by promoter methylation in many types of tumors, yet ASC's role in most cancers remains unknown. Here, we show that ASC is highly expressed in a model of medulloblastoma, the most common malignant pediatric brain cancer; ASC is also expressed in human medulloblastomas. Importantly, while ASC deficiency did not affect normal cerebellar development, ASC knockout mice on the Smoothened (ND2:SmoA1) transgenic model of medulloblastoma exhibited a profound reduction in medulloblastoma incidence and a delayed tumor onset. A similar decrease in tumorigenesis with ASC deficiency was also seen in the hGFAP-Cre:SmoM2 mouse model of medulloblastoma. Interestingly, hyperproliferation of the external granule layer (EGL) was comparable at P20 in both wild-type and ASC-deficient SmoA1 mice. However, while the apoptosis and differentiation markers remained unchanged at this age, proliferation makers were decreased, and the EGL was reduced in thickness and area by P60. This reduction in proliferation with ASC deficiency was also seen in isolated SmoA1 cerebellar granule precursor cells in vitro, indicating that the effect of ASC deletion on proliferation was cell autonomous. Interestingly, ASC-deficient SmoA1 cerebella exhibited disrupted expression of genes in the transforming growth factor-ß pathway and increased level of nuclear Smad3. Taken together, these results demonstrate an unexpected role for ASC in Sonic hedgehog-driven medulloblastoma tumorigenesis, thus identifying ASC as a promising novel target for antitumor therapy.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Proliferación Celular , Neoplasias Cerebelosas/genética , Meduloblastoma/genética , Adolescente , Adulto , Animales , Proteínas Reguladoras de la Apoptosis/deficiencia , Proteínas Adaptadoras de Señalización CARD , Neoplasias Cerebelosas/metabolismo , Neoplasias Cerebelosas/patología , Niño , Preescolar , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación in Situ , Lactante , Masculino , Meduloblastoma/metabolismo , Meduloblastoma/patología , Ratones Noqueados , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Adulto JovenRESUMEN
Neurogenesis requires negative regulation through differentiation of progenitors or their programmed cell death (PCD). Growth regulation is particularly important in the postnatal cerebellum, where excessive progenitor proliferation promotes medulloblastoma, the most common malignant brain tumor in children. We present evidence that PCD operates alongside differentiation to regulate cerebellar granule neuron progenitors (CGNPs) and to prevent medulloblastoma. Here, we show that genetic deletion of pro-apoptotic Bax disrupts regulation of cerebellar neurogenesis and promotes medulloblastoma formation. In Bax(-/-) mice, the period of neurogenesis was extended into the third week of postnatal life, and ectopic neurons and progenitors collected in the molecular layer of the cerebellum and adjacent tectum. Importantly, genetic deletion of Bax in medulloblastoma-prone ND2:SmoA1 transgenic mice greatly accelerated tumorigenesis. Bax-deficient medulloblastomas exhibited strikingly distinct pathology, with reduced apoptosis, increased neural differentiation and tectal migration. Comparing Bax(+/+) and Bax(-/-) medulloblastomas, we were able to identify upregulation of Bcl-2 and nuclear exclusion of p27 as tumorigenic changes that are required to mitigate the tumor suppressive effect of Bax. Studies on human tumors confirmed the importance of modulating Bax in medulloblastoma pathogenesis. Our results demonstrate that Bax-dependent apoptosis regulates postnatal cerebellar neurogenesis, suppresses medulloblastoma formation and imposes selective pressure on tumors that form. Functional resistance to Bax-mediated apoptosis, required for medulloblastoma tumorigenesis, may be a tumor-specific vulnerability to be exploited for therapeutic benefit.
Asunto(s)
Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Meduloblastoma/genética , Meduloblastoma/patología , Neurogénesis/genética , Proteína X Asociada a bcl-2/genética , Animales , Apoptosis/genética , Diferenciación Celular/genética , Movimiento Celular/genética , Neoplasias Cerebelosas/metabolismo , Cerebelo/citología , Cerebelo/metabolismo , Cerebelo/patología , Regulación hacia Abajo , Meduloblastoma/metabolismo , Ratones , Ratones Transgénicos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptor Smoothened , Células Madre/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
We report the third documented case of small bowel entrapment within a sacral fracture leading to small bowel obstruction. This important diagnosis is rare and difficult to make, even with current imaging methods. We report a case in which a segment of small bowel trapped in a Denis II fracture of the sacrum required laparotomy, small bowel resection, and an omental patch over the fracture site. In this case the outcome was favorable with no residual sequelae.
